tbuckley/cabot-search huggingface dataset:
Abstract 5201: TNFR2 humanized mice: an ideal model for studying anti-TNFR2 antibodies
Authors: Huiyi Wang, Ying Li, Mingkun Zhang, Xu Su, Santi Suryani Chen, Zhiying Li, Mark Wade Moore, Jing Zhao, Xiang Gao, Cunxiang Ju
Journal: Cancer Research (2023)

Abstract Tumor necrosis factor (TNF) receptor 2 (TNFR2) is mainly expressed on the surface of regulatory T cells (Tregs) and CD8+ T cells, which can stimulate the proliferation of these cells through NF-kB activation. TNFR2 is also highly expressed on the surface of various human tumors, such as colorectal cancer and lung cancer. Therefore, a TNFR2 antagonist blocking the binding of TNFR2 to its ligand that targets TNFR2+ tumor-infiltrating Tregs can directly enhance the killing ability of effector T cells (Teff) against TNFR2-expressing tumors. Many pharmaceutical and biotech companies have lined up TNFR2-targeting drugs, and most TNFR2 antibodies related research is in the early preclinical/clinical stage. We established a humanized TNFR2 (hTNFR2) genetically engineered mouse model on the BALB/c background, in which the extracellular domain of the mouse TNFR2 was replaced with its human counterpart, and the murine transmembrane and cytoplasmic domain kept intact. The hTNFR2 chimeric protein is mainly expressed on Teff and Treg cells in BALB/c-hTNFR2 and BALB/c-hPD1/hPDL1/hTNFR2 mice, which is similar to mouse TNFR2 protein expression profiles in wild-type mice. Our data showed that anti-TNFR2 antibodies could significantly inhibit tumor growth in BALB/c-hTNFR2 mice bearing CT26 tumor cells or BALB/c-hTNFR2 mice bearing CT26-hTNFR2 tumors. Furthermore, within the tumor-infiltrating lymphocytes, there was a reduction in Tregs cells and an increase in cytotoxic CD8 T cells, which accurately mimics the mechanism of action of anti-TNFR2 antibodies. In conclusion, BALB/c-hTNFR2 and BALB/c-hPD1/hPDL1/hTNFR2 mice are ideal models for studying the efficacy and pharmacodynamics of anti-TNFR2 antibodies as a single agent or in combination with anti-PD-1/PD-L1 therapies. Citation Format: Huiyi Wang, Ying Li, Mingkun Zhang, Xu Su, Santi Suryani Chen, Zhiying Li, Mark Wade Moore, Jing Zhao, Xiang Gao, Cunxiang Ju. TNFR2 humanized mice: an ideal model for studying anti-TNFR2 antibodies. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5201.
Abstract 1806: Modulation of natural killer cell immune response to tumor with novel synthetic tumor -immune cell agonist, NK-TICA(r)
Authors: Fay Dufort, Christopher J. Leitheiser, Kathleen Ho, Tucker Ezell, Alexandra Rezvaya, Peter Brown, Liuhong Chen, Philip Brandish, Kevin McDonnell, Michael Skynner, Nicholas Keen
Journal: Cancer Research (2023)

Abstract The tumor specific activation of natural killer (NK) cells with Bicycles is an area of active investigation in immune oncology. NK cells are highly responsive immune cells that can detect and eliminate tumor cells and bridge innate to adaptive immune responses. Bicycles are small (ca.1.5kDa), chemically synthetic, structurally constrained peptides discovered via phage display and optimized using structure-driven design and medicinal chemistry approaches. We have applied the Bicycle platform technology to discover and evaluate a new class of fully synthetic molecules termed NK tumor immune cell agonists (NK-TICA®). The NK-TICA® consists of chemically coupled Bicycles® that bind specifically to the key activating receptor, NKp46, and to tumor antigens, that results in highly potent, antigen-dependent receptor activation and NK cell activation. We demonstrate potent, selective binding of our Bicycles to receptor-expressing cells and the capability of the bifunctional molecule to induce NK cell function in vitro. With Bicycle’s novel NK-TICA® compound, we demonstrate the engagement of NK cells, the specific activation and function of NK cells, and enhanced tumor cytotoxicity in a tumor target- and dose-dependent manner. In conclusion, NK-TICAs drive NK cell-mediated tumor cell killing and cytokine production in vitro and as such have the potential to catalyze the development of durable anti-tumor immunity in tumor types not well served by current therapies. We hypothesize that utilization of Bicycle NK-TICA® as a multifunctional immune cell engager will promote the modulation of NK cells, as well as the infiltration and anti-tumor activity of NK cells in solid tumors. Citation Format: Fay Dufort, Christopher J. Leitheiser, Kathleen Ho, Tucker Ezell, Alexandra Rezvaya, Peter Brown, Liuhong Chen, Philip Brandish, Kevin McDonnell, Michael Skynner, Nicholas Keen. Modulation of natural killer cell immune response to tumor with novel synthetic tumor -immune cell agonist, NK-TICA(r) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1806.
Abstract 3831: The molecular composition of a water-soluble extract from the leaves of the indigenous Southern African plant <i>Tulbaghia violacea</i> that displays anti-cancer activity against a triple negative breast cancer cell line
Authors: Mohammed Alaouna, Clement Penny, Rodney Ulll, Zodwa Dlamini
Journal: Cancer Research (2023)

Abstract Approximately 20% of all breast cancer cases are Triple negative breast cancer (TNBC), whichis more difficult to treat and has a higher mortality rate than other types of breast cancer. Thereis an active practice of traditional medicine in in South Africa, in the form of infusions madeusing plant material. Previously we demonstrated that water soluble extracts from the leaves ofone of these plants, African garlic (Tulbaghia violacea), is able to induce apoptosis in TNBCcell lines, while also inhibiting the ability of these cells to migrate or penetrate a basementmembrane. In an attempt to isolate the molecular compounds that are present in this extract,water soluble leaf extracts were subjected to Fourier transform infrared spectroscopy (FITR),Gas chromatography–mass spectrometry (GC-MS) and Nuclear magnetic resonance (NMR)spectroscopy. Identified compounds of interest were then used in computational dockingstudies with the anti-apoptotic protein Cox2. The FITR analysis indicated that the extractconsisted of multiple compounds, belonging to a variety of classes. GC-NS and NMRspectroscopy identified 36 and 61 separate compounds respectively. Many of these compoundswere similar in structure to compounds with known anti-cancer properties. Many compoundswith established medical uses were also identified in the extract. Five compounds identified inthe extract, d-Glycero-d-galacto-heptose, H-Pyran-4-one, 2,3-dihydro-3,5-dihydroxy-6-methyl, and Benzaldehyde and 4-(1-methylethyl)- demonstrated high binding affinity towardsCOX2. With d-Glycero-d-galacto-heptose having a higher docking score than manycommercially available COX2 inhibitors. Based on our findings, the compounds within theextract could be used as the basis for the development of safe and effective drugs for thetreatment of TNBC and other cancers. In order to fulfil this potential, future work shouldexamine the molecular pathways affected by the treatment of TNBC cells with this extract orindividual compounds. Citation Format: Mohammed Alaouna, Clement Penny, Rodney Ulll, Zodwa Dlamini. The molecular composition of a water-soluble extract from the leaves of the indigenous Southern African plant Tulbaghia violacea that displays anti-cancer activity against a triple negative breast cancer cell line. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3831.
Abstract 3819: Naringin nanoparticles inhibit metastasis of lung cancer through TGF-β1-smad2/3 signaling pathway
Authors: Wen Chen
Journal: Cancer Research (2023)

Abstract Lung cancer causes high mortality due to its high metastasis. Naringin is a naturally occurring flavonoid that is widely found in the various citrus fruits. Naringin is known to have several therapeutic effects including anticancer, anti-pulmonary fibrosis, antimicrobial, anti-inflammatory. However, low bioavailability and solubility of naringin limit its application. This project designed a thermosensitive naringin nanoparticle to investigate whether it might inhibit metastasis of lung cancer by inhibiting TGF-β1-smad2/3 signaling pathway. Cells were treated with various concentrations of naringin nanoparticles and unwrapped naringin for 48 hours. Naringin nanoparticles of 100µmol/L showed obvious inhibitory effect on the larger wound surface of cultured human cancer cells. Westerm blot was used to detect the expression of P-Smad2, Smad2,and α-SMA in A549 cells. The results showed that naringin significantly reduced the expression of EMT-related protein α-SMA in A549 cells in a concentration-dependent manner. Naringin nanoparticles can reverse the EMT process. naringin nanoparticles can inhibit the expression of P-Smad2 protein in A549 cells, which may play a role in inhibiting lung cancer through TGF-β1/Smad signaling pathway.The animal experiment was performed. The mice were given various concentrations of naringin nanoparticles and unwrapped naringin by IV. the protein expression levels of α-SMA, TGF-β1 and P-Smad3 in mice lung tissue were detected by immunohistochemistry. The results showed that naringin nanoparticles 50um/ml,0.2mL/day/time had significant effect on the inhibition of lung cancer tissue migration, and the different doses of naringin nanoparticles showed a certain dose-dependent trend. The expression of TGF-β1 and P-Smad3 in mice treated with naringin nanoparticles was significantly decreased, suggesting that naringin nanoparticles could inhibit the migration of lung cancer cells by inhibiting TGF-β1/Smad pathway. Citation Format: Wen Chen. Naringin nanoparticles inhibit metastasis of lung cancer through TGF-β1-smad2/3 signaling pathway. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3819.
Abstract 5718: Additivity predicts the clinical efficacy of most approved combination therapies for advanced cancer
Authors: Haeun Hwangbo, Sarah Patterson, Andy Dai, Deborah Plana, Adam C. Palmer
Journal: Cancer Research (2023)

Abstract Most advanced cancers are treated with drug combinations. Rational designs aim to identify synergistic drug interactions to produce superior treatments. However, metrics of drug interaction (i.e., synergy, additivity, antagonism) apply to pre-clinical experiments, and there has been no established method to quantify synergy versus additivity in clinical settings. Here, we propose and apply a model of drug additivity for progression-free survival (PFS) to assess if the clinical efficacies of approved drug combinations are more than, or equal to, the sum of their parts. This model accounts for the benefit from patient-to-patient variability in the best single drug response, plus the added benefit of the weaker drug per patient. Among all FDA approvals of combination therapies for advanced cancer between 1995 and 2020, we identified 37 combinations across 13 cancer types (24,723 patients) where the efficacies of monotherapies and combination therapies could be analyzed at matched doses. 95% of combination therapies exhibited progression-free survival times that were additive, or less than additive. Across all trials and follow-up times, the coefficient of determination of the additivity model was R2=0.90, with no fitting or training, only the operation of addition. While there were deviations from additivity, with several combinations being less than additive, 100% of the approved combinations studied would have been predicted to succeed by the additivity model. This study has two key findings. First, a synergistic effect (more than additive) is neither a necessary nor even common property of clinically effective drug combinations. Second, the predictable efficacy of many of the best drug combinations established over the past 25 years suggests that additivity can be used as a design principle for novel drug combinations and clinical trials, which could be helpful as the number of possible therapies grows and as cancers are increasingly divided into subtypes with distinct drug sensitivities. Citation Format: Haeun Hwangbo, Sarah Patterson, Andy Dai, Deborah Plana, Adam C. Palmer. Additivity predicts the clinical efficacy of most approved combination therapies for advanced cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5718.
Abstract 1499: HOXC6 gene functions as an oncogenic driver in HPV+ head and neck squamous cell carcinoma (HNSCC)
Authors: Subhendu Roy Choudhury, Vera Mukhina, Iuliia Vyshkvorkina, Jessica Gore, Alexa Anderson, Daria A. Gaykalova
Journal: Cancer Research (2023)

Abstract Homeobox C6 (HOXC6) belongs to the member of the homeobox family, a highly conserved transcription factor that plays an essential role in morphogenesis and cellular differentiation during embryonic development. Previous studies reported that the dysregulation of HOXC6 gene expression plays a crucial role in carcinogenesis. HOXC6 is reportedly over-expressed in several types of human cancer, including breast, leukemia, and lung cancers. Moreover, higher expression of HOXC6 leads to lymph node metastasis. In addition, it has been also demonstrated that in prostate cancer cells, HOXC6 downregulation reduced cell proliferation by inducing apoptosis. Although the precise mechanisms of HOXC6 in carcinogenesis still need to be investigated. In a secondary data analysis from our previous study, we identified HOXC6 is upregulated and enriched with tumor type-specific enhancer region in HPV+HNSCC samples. Moreover, we used publicly available TCGA data consisting of 520 HNSCC samples and a JHU cohort with 47 HPV+ HNSCC samples to illustrate that HOXC6 is more highly expressed in HPV+ HNSCC than in adjacent normal samples. We further validated the HOXC6 overexpression through an in vitro study using HPV+HNSCC cell lines and patient tissue samples. Clinicopathological data from TCGA indicated that higher HOXC6 expression correlated with poor overall survival. To explore the function of HOXC6 in HNSCC, we knocked down HOXC6 in HPV+ HNSCC cells via siRNA and performed the cell proliferation assay. We observed that HOXC6 downregulation decreased the cell proliferation rate compared to control samples. In conclusion, our results suggest HOXC6 acts as an oncogenic driver in HPV+ HNSCC progression, which is potentially regulated by tumor type-specific enhancers and may serve as a potential biomarker. Citation Format: Subhendu Roy Choudhury, Vera Mukhina, Iuliia Vyshkvorkina, Jessica Gore, Alexa Anderson, Daria A. Gaykalova. HOXC6 gene functions as an oncogenic driver in HPV+ head and neck squamous cell carcinoma (HNSCC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1499.
Abstract 3832: Apoptotic and cell cycle effects of triterpenes isolated from <i>Phoradendron wattii</i> on a chronic myelogenous leukemia cell line
Authors: Rosa E. Moo-Puc, Shirley A. Calderón Sauri, Jairo R. Villanueva-Toledo, Sergio R. Peraza-Sánchez, Antonieta Chávez-González
Journal: Cancer Research (2023)

Abstract Introduction: Medicinal plants have been used in traditional medicine practices since ancient times. Mayan traditional medicine uses herbs as treatment to illness that can be related to cancer disease such as Phoradendron wattii. As part of the search for novel cancer treatment two triterpene compounds were isolated from P. wattii: 3-epi-betulinic acid and lupenone with preliminary activity on leukemias. We investigated the cancer treatment abilities of 3-epi-betulinic acid and lupenone on human chronic myelogenous leukemia (K562) cell line and monocytes isolated from peripheral blood using flow cytometry methods. Results: Lupenone showed low effect on both cells with an IC50 of 177.60 ± 5.07 µg/mL and a selectivity index (SI) of 0.10 times more on K-562 cell line than on monocytes. Nevertheless, 3-epi-betulinic acid showed a moderate anti-CML activity with an IC50 of 38.74 ± 5.07 µg/mL, having a SI of 4.10 on K-562 cells when compared to monocytes. These results indicate that 3-epi-betulinic acid was 41 times more selective for K-562 cell line than lupenone and it also was 7.45 more selective than etoposide as positive control. Additionally, 3-epi-betulinic acid increased cell population in the G0/G1 phase of the cell cycle and apoptotic cells, and it inhibited cell proliferation in a dose-dependent manner. Furthermore, the relative expression of genes associated with apoptosis Bax and caspase 3 increased compared to control. Conclusion: Combined, these results suggest that 3-epi-betulinic acid plays an important regulatory role of cell cycle and apoptosis. Finally, the 3-epi-betulinic acid investigated in this work is potentially a cheap, safe, and effective alternative to chemotherapy in cancer treatment. Citation Format: Rosa E. Moo-Puc, Shirley A. Calderón Sauri, Jairo R. Villanueva-Toledo, Sergio R. Peraza-Sánchez, Antonieta Chávez-González. Apoptotic and cell cycle effects of triterpenes isolated from Phoradendron wattii on a chronic myelogenous leukemia cell line. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3832.
Abstract 470: A MDM2 degrader inhibits cell proliferation and growth of MDM2-overexpressing acute lymphoblastic leukemia in SCID mice
Authors: tao Liu, Lubing Gu, Anna Mui, Zhongzhi Wu, Wei Li, Muxiang Zhou
Journal: Cancer Research (2023)

Abstract The MDM2 oncogene is amplified and/or overexpressed in various human cancers and elevated expression of MDM2 protein acts as a survival factor promoting cancer progression mainly through inhibition of the tumor suppressor p53. Here, we report a novel small-molecule chemical compound (MX69-114b) that we identified to induce MDM2 protein degradation resulting in reactivation of p53 and potent cell growth inhibition and apoptosis in MDM2-overexpressing acute lymphoblastic leukemia (ALL). We have previously identified a compound (MX69) that binds to the MDM2 C-terminal RING domain and induces MDM2 protein degradation. In the present study, we performed structural modification of MX69 and selected analog MX69-114b showing increased MDM2-targeting activity. MX69-114b exhibited significantly enhanced inhibitory and apoptotic effects on a group of MDM2-overexpressing ALL cell lines in vitro with IC50 values of 0.08-0.14 µM, representing a &amp;gt;80-100-fold increase in activity compared to MX69. MX69-114b also showed inhibitory effects on xenografted human MDM2-overexpressing ALL in SCID mice at a much lower dose than did MX69. Importantly, MX69-114b had minimal or no inhibitory effect on normal human hematopoiesis in vitro and was very well tolerated in vivo in animal models. Based on the strong inhibitory and apoptotic activity against MDM2-overexpressing ALL, along with minimal or no toxicity to normal cells/tissues, MX69-114b is a candidate for further development as a novel MDM2-targeted therapeutic drug for refractory ALL. Citation Format: tao Liu, Lubing Gu, Anna Mui, Zhongzhi Wu, Wei Li, Muxiang Zhou. A MDM2 degrader inhibits cell proliferation and growth of MDM2-overexpressing acute lymphoblastic leukemia in SCID mice [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 470.
Abstract 3851: Targeting RET solvent-front mutants with an alkynyl nicotinamide-based inhibitor
Authors: Ujjwol Khatri, Neetu Dayal, Xueqing Hu, Elizabeth Larocque, Nimishetti Naganna, Tao Shen, Xuan Liu, Frederick W. Holtsberg, M. Javad Aman, Herman O. Sintim, Jie Wu
Journal: Cancer Research (2023)

Abstract Selpercatinib (LOXO-292, LY3527723) and pralsetinib (BLU-667) are first-in-class RET-targeted cancer therapy drugs. However, secondary RET mutations that confer selpercatinib/pralsetinib resistance have been identified, necessitating development of next-generation RET Tyrosine kinase inhibitors (TKIs). While the G810C/R/S/V mutations located at the RET kinase solvent-front site were detected in selpercatinib-treated patients, it was unclear whether all of these and other potential G810 mutants are resistant to selpercatinib and pralsetinib. We profiled selpercatinib and pralsetinib on all six possible G810 mutants derived from single nucleotide substitution. Surprisingly, the G810V mutant found in a clinical study was not resistant to selpercatinib or pralsetinib. Besides G810C/R/S, G810D also conferred selpercatinib/pralsetinib resistance. We found that alkynyl nicotinamide compounds such as HSN608 have better drug-like properties than alkynyl benzamides. HSN608 inhibited RET and RET V804M gatekeeper mutant, and all six G810 mutants with low nanomolar IC50s in the BaF3/KIF5B-RET mutant cell model. In cell derived xenograft (CDX) tumors driven by KIF5B-RET(G810C), HSN608 caused regression of the selpercatinib-resistant tumors. This study clarifies the sensitivities of different RET solvent-front mutants to selpercatinib and pralsetinib, and identifies an alkylnyl nicotinamide-based RET TKI for inhibiting selpercatinib/pralsetinib-resistant G810 mutants. Citation Format: Ujjwol Khatri, Neetu Dayal, Xueqing Hu, Elizabeth Larocque, Nimishetti Naganna, Tao Shen, Xuan Liu, Frederick W. Holtsberg, M. Javad Aman, Herman O. Sintim, Jie Wu. Targeting RET solvent-front mutants with an alkynyl nicotinamide-based inhibitor. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3851.